This invention relates to methods of treating neuronal inflammatory disorders.
Certain hydroxyalkyiquinoline acids and ether acids, as well as their corresponding salts, are known to be leukotriene antagonists. See, e.g., U.S. Pat. Nos. 5,266,568, 5,270,324, 5,428,033, 5,565,473 and 5,856,322. As noted in the foregoing patents, these compounds are known to be useful in the treatment of pulmonary disorders including diseases such as asthma, chronic bronchitis, and related obstructive airway diseases, allergies and allergic reactions such as allergic rhinitis, contact dermatitis, allergic conjunctivitis, and the like, inflammation such as arthritis or inflammatory bowel disease, pain, skin disorders such as psoriasis, a topic eczema, and the like, cardiovascular disorders such as angina, myocardial ischemia, hypertension, platelet aggregation and the like, renal insufficiency arising from ischemia induced by immunological or chemical (cyclosporin) etiology, migraine or cluster headache, ocular conditions such as uveitis, hepatitis resulting from chemical, immunological or infectious stimuli, trauma or shock states such as burn injuries, endotoxemia and the like, allograft rejection, prevention of side effects associated with therapeutic administration of cytokines such as Interleukin II and tumor necrosis factor, chronic lung diseases such as cystic fibrosis, bronchitis and other small and large-airway diseases, cholecystitis; erosive gastritis; erosive esophagitis; diarrhea; cerebral spasm; premature labor; spontaneous abortion; dysmenorrhea; ischemia; noxious agent-induced damage or necrosis of hepatic, pancreatic, renal, or myocardial tissue; liver parenchymal damage caused by hepatoxic agents such as CCl4 and D-galactosamine; ischemic renal failure; disease-induced hepatic damage; bile salt induced pancreatic or gastric damage; trauma-or stress-induced cell damage; glycerol-induced renal failure; and cytoprotective activity in gastrointestinal mucosa and prevention of gastric lesions.
However, it has now been found that select hydroxyalkylquinoline acids (and the pharmaceutically acceptable salts thereof) are useful in the treatment of conditions which are believed to be caused by neuronal inflammation. Neuronal inflammatory disorders share a particular pathophysiology in relation to the select hydroxyalkylquinoline compounds. In particular, compounds which have the biological property in mammals of acting as xe2x80x9cleukotriene antagonistsxe2x80x9d are particularly effective in the treatment of neuronal inflammatory disorders.
Furthermore, it has been discovered that certain hydroxyalkylquinoline acids and their salts can be utilized to treat some disorders which have not been conclusively shown to originate with inflamed neurons. One particularly painful and debilitating group of disorders, members of which have responded remarkably well to treatment with hydroxyalkylquinolines, are those commonly referred to as repetitive motion disorders. In the case of such disorders, hydroxyalkylquinolines not only effectively relieve the symptoms, but often effect a complete cure, allowing return to the same repetitive motion-type activity which caused the disorder without incidence of relapse. Regardless of any previous association with repetitive motion, the disorders referred to hereinafter are considered to be neuronal inflammatory disorders for the purposes of this description, even if it has not been conclusively established that the symptoms of the particular disorder are caused or mediated by inflamed neuronal elements.
Disorders which are known to be neural inflammatory in nature include viral infections, such as Herpes simplexes I and II. The present invention has demonstrated success in the treatment of symptoms of viral infections. Thus a method is provided for the treatment and/or the long term suppression of symptoms of viral infection such as skin lesions and postherpetic neuralgia, as well as other symptoms of viral infection which are neuronal inflammatory in origin.
The present invention has also been successful in halting the course of a condition which has long been suspected by the present inventor to be neuronal inflammatory in origin: the progressive graying of the scalp hair. Thus the present invention provides a method for the treatment and/or long-term suppression of symptoms of scalp hair conditions which are neuronal inflammatory in nature, such as progressive graying.
In addition, the present invention provides a method for treating and/or suppression of symptoms of neuronal inflammatory conditions whose etiology is often partially or fully unknown, some of which are Multiple sclerosis, Guillian-Barre syndrome and Bell""s palsy.
Furthermore, the present invention provides a method for the treatment of neuronal inflammatory conditions which originate with external factors, such conditions including traumatic spinal injury.
Moreover, the present invention provides a method for treatment and long term suppression of symptoms associated with disorders previously considered repetitive motion disorders.
The above-described methods comprise administering, to a mammal in need of such treatment, a therapeutically effective amount of a compound having a chemical structural formula as follows: 
wherein:
R1 is H, halogen, xe2x80x94CF3, xe2x80x94CN, xe2x80x94NO2, or N3;
R2 is lower alkyl, lower alkenyl, lower alkynyl, xe2x80x94CF3, xe2x80x94CH2F, xe2x80x94CHF2, CH2CF3, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted 2-phenethyl, or two R2 groups joined to the same carbon to form a carbocyclic ring of up to 8 members;
R3 is H or R2;
R4 is halogen, xe2x80x94NO2, xe2x80x94CN, xe2x80x94OR3, xe2x80x94SR3, NR3R3, NR3C(O)R7 or R3;
R5is H, halogen, xe2x80x94NO2, xe2x80x94N3, xe2x80x94CN, xe2x80x94SR2, NR3R3, xe2x80x94OR3, lower alkyl, or xe2x80x94C(O)R3;
R6 is xe2x80x94(CH2)5 xe2x80x94C(R7R7)xe2x80x94(CH2), xe2x80x94R8 or xe2x80x94CH2C(O)NR12R12;
R7 is H or C1-C4 alkyl;
R8 is the radical Wxe2x80x94R9; 
R9 contains up to 20 carbon atoms and is (1) an alkyl group or (2) an alkylcarbonyl group of an organic acyclic or monocyclic carboxylic acid;
R11 is lower alkyl, xe2x80x94C(O)R14, unsubstituted phenyl, or unsubstituted benzyl;
R12 is H, or R11;
R13 is lower alkyl, lower alkenyl, lower alkynyl, xe2x80x94CF3 or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R14 is H or R13;
R16 is H, C1-C4 alkyl, or OH;
R17 is lower alkyl, lower alkenyl, lower alkynyl, or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R18 is lower alkyl, lower alkenyl, lower alkynyl, xe2x80x94CF3 or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R19 is lower alkyl, lower alkenyl, lower alkynyl, xe2x80x94CF3 or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;
R21 is H or R17;
R22 is R4, CHR7OR3, or CHR7 SR2;
m is 0-8;
mxe2x80x2 is 2 or 3;
n and nxe2x80x2 are independently 0 or 1,
p and pxe2x80x2 are independently 0-8;
m+n+p is 1-10 when r is 1 and X2 is O, S, S(O), or S(O)2;
m+n+p is 0-10 when r is 1 and X2 is CR3R16;
m+n+p is 0-10 when r is 0;
mxe2x80x2+nxe2x80x2+pxe2x80x2 is 2-10;
r and rxe2x80x2 are independently 0 or 1;
s is 0-3;
Q1 is xe2x80x94C(O)OR3, 1H (or 2H)-tetfazol-5-yl, xe2x80x94C(O)OR6, xe2x80x94C(O)NHS(O)2R13, xe2x80x94CN, xe2x80x94C(O)NR12R12, NR21 S(O)2R13, xe2x80x94NR12C(O)NR12R12, xe2x80x94NR21C(O)R18, xe2x80x94OC(O)NR12R12, xe2x80x94C(O)R19, xe2x80x94S(O)R18, xe2x80x94S(O)2R18, xe2x80x94S(O)2 NR12R12, xe2x80x94NO2, xe2x80x94NR21C(O)OR17, xe2x80x94C(NR12R12)xe2x95x90NR12, xe2x80x94C(R13)xe2x95x90NOH;
Q2 is OH;
W is O, S, or NR3;
X2 and X3 are independently O, S, S(O), S(O)2, or CR3R16; with the proviso that at least on is S or SO2;
Y is xe2x80x94CR3xe2x95x90CR3xe2x80x94
Z1 and Z2 are independently xe2x80x94HET(xe2x80x94R3xe2x80x94R5)xe2x80x94;
HET is the diradical of a benzene, a pyridine, a furan, or a thiophene;
or a pharmaceutically acceptable salt thereof. The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects, e.g., an acid or base addition salt.
Preferred is a compound having a chemical structural formula as follows: 
wherein the substituents are as follows:
Particularly preferred as the compound is 1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy- 2-propyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid or a pharmaceutically acceptable salt thereof, and in particular the monosodium salt thereof (i.e., montelukast sodium), which is the active ingredient in the pharmaceutical marketed by Merck and Co., Inc. under the trademark, Singulair(copyright). This and related compounds, including methods of producing such compounds, are described in greater detail in U.S. Pat. No. 5,565,473, the disclosure of which is incorporated herein by reference.
This invention also provides an article of manufacture for human pharmaceutical use, comprising packaging material and a container comprising 1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid or a pharmaceutically acceptable salt thereof, wherein said packaging material comprises a label which indicates that said cyclopropaneacetic acid, or said pharmaceutically acceptable salt thereof, is suitable for treatment, or alleviation of symptoms, often or more disorders selected from the group consisting of carpal tunnel, cubital tunnel, tarsal tunnel, traumatic spinal cord injury, graying of scalp hair, thoracic outlet, herpes simplex, herpes zoster, Bell""s palsy, multiple sclerosis, and Gillian-Barre.